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Erectile Dysfunction in a Murine Model of Sleep Apnea

¹ Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, Kentucky; ² Department of General Physiology, St. Petersburg State University, St. Petersburg, Russia; and ³ Department of Obstetrics and Gynecology, and ⁴ Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky

Correspondence and requests for reprints should be addressed to David Gozal, M.D., University of Louisville, Department of Pediatrics, KCHRI, 570 S. Preston Street, Suite 204, Louisville, KY 40202. E-mail: david.gozal{at}louisville.edu

Rationale: Erectile dysfunction (ED) is frequent in obstructive sleep apnea syndrome (OSAS). Chronic intermittent hypoxia (CIH), one of the hallmarks of OSAS, could mediate ED.

Objectives: To determine whether intermittent hypoxia during sleep affects erectile dysfunction in mice.

Methods: Three groups of C57BL/6 mice were exposed to CIH for 5 or 24 weeks. Sexual function was evaluated by in vivo telemetry of corpus spongiosum pressure. Spontaneous erections, sexual activity during mating, and noncontact tests were assessed after 5 weeks of CIH and after treatment with tadalafil. Plasma testosterone was measured after 8 and 24 weeks of CIH, and the expression of nitric oxide synthase (NOS) isoforms was examined in penile tissue.

Measurements and Main Results: Noncontact, spontaneous, and contact sexual activity in the mice was suppressed after CIH. Spontaneous erection counts decreased after the first week of CIH by 55% (P < 0.001) and remained unchanged thereafter. Recovery of erectile activity during normoxia for 6 weeks was incomplete. Compared with control mice, latencies for mounts and intromissions increased by 60- and 40-fold, respectively (P < 0.001), and the sexual activity index decreased sixfold. Tadalafil treatment significantly attenuated these effects. Immunoblot analyses of NOS proteins in the erectile tissue showed decreased expression of endothelial NOS after CIH (P < 0.01), with no changes in plasma testosterone levels after 8 and 24 weeks of CIH.

Conclusions: CIH during sleep is associated with decreased libido in mice. The decreased expression of endothelial NOS protein in erectile tissue and the favorable response to tadalafil suggest that altered nitric oxide mechanisms underlie CIH-mediated ED. No changes in testosterone emerge after intermittent hypoxia.

Key Words: nitric oxide synthase • erectile dysfunction • sleep apnea • intermittent hypoxia

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Erectile dysfunction is a frequent occurrence in male patients with obstructive sleep apnea; however, potential mechanisms mediating this morbidity are currently unknown. What This Study Adds to the Field A novel murine model that allows for sexual function assessment in freely behaving males was exposed to a model of sleep apnea and showed the emergence of marked alterations in sexual drive and erectile dysfunction that was responsive to tadalafil.